Summary: The Leishmania parasite causes human disease with clinical symptoms ranging from-self healing cutaneous lesions to a fatal visceral infection. Additionally, in endemic areas, people infected with HIV are especially prone to Leishmania infection and latent infections can reactivate upon acquisition of HIV. The lack of understanding of cell biology and pathogenic mechanisms of this parasite makes the task of controlling this grave, worldwide health risk difficult. Closer to home, it is particularly of concern to U.S. military personnel, their families and other travellers visiting or living in the endemic areas. To find novel methods for control of this pathogen, we have initiated study to understand the mechanism of parasite differentiation from the avirulent (promastigote) to virulent (amastigote) form. Membrane or secretory proteins of Leishmania have been implicated for its defense mechanism against killing by the host. Very little is known about the importance of gylcosyation/folding and intracellular transport of membrane and secretory proteins in Leishmania. ER resident chaperone proteins are known to play an essential role in these processes. Further we argued that alteration of the secretion process might result in attenuation of virulence in Leishmania. We have cloned several homologues of such chaperone proteins such as calreticulin and protein disulfide isomerase (PDI) from Leishmania donovani. Expression of dominant negative forms of calreticulin or PDI in Leishmania affected the secretion of one of the essential secretory proteins, s-acid phosphatase (sAcP). Such parasites were shown to be more prone to killing by the macrophages. These studies suggest that alteration in the secretion of Leishmanial putative virulent factors can result in the attenuation of its infectivity.